| Structural highlights
9c8t is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.47Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
CGAS_HUMAN Nucleotidyltransferase that catalyzes formation of cyclic GMP-AMP (cGAMP) from ATP and GTP and exhibits antiviral activity. Has antiviral activity by acting as a key cytosolic DNA sensor, the presence of DNA in the cytoplasm being a danger signal that triggers the immune responses. Binds cytosolic DNA directly, leading to activation and synthesis of cGAMP, a second messenger that binds to and activates TMEM173/STING, thereby triggering type-I interferon production.[1] [2]
Publication Abstract from PubMed
Cyclic GMP-AMP synthase (cGAS) is an intracellular sensor of double-stranded DNA that triggers a pro-inflammatory response upon binding. The interest in cGAS as a drug discovery target has increased substantially over the past decade due to growing evidence linking its activation to numerous peripheral and neurological diseases. Here, we report the binding mode of previously described cGAS inhibitors while also uncovering the structural basis for the interspecies potency shifts within this chemotype. A single threonine to isoleucine substitution between human and mouse cGAS drives compound activity, as demonstrated by biochemical, cellular, and in vivo studies. Finally, we utilize a structurally enabled design approach to engineer a novel chemical inhibitor with excellent potency for both human and mouse enzymes by targeting key interactions within the enzyme active site. Overall, this work provides the framework for rational optimization of cGAS inhibitors and potential preclinical translational strategies.
Structural insight into the cGAS active site explains differences between therapeutically relevant species.,Skeldon AM, Wang L, Sgarioto N, Beveridge RE, Chan S, Dorich S, Dumais V, Fradet N, Gaudreault S, LeGros P, McKay D, Seliniotakis R, Sietsema DV, Zhang L, Boily MO, Burch JD, Caron A, Fader LD, Lama L, Xie W, Patel DJ, Tuschl T, Crackower MA, Pike KA Commun Chem. 2025 Mar 22;8(1):88. doi: 10.1038/s42004-025-01481-7. PMID:40121343[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011 Apr 28;472(7344):481-5. doi: 10.1038/nature09907. Epub 2011 Apr 10. PMID:21478870 doi:10.1038/nature09907
- ↑ Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013 Feb 15;339(6121):786-91. doi: 10.1126/science.1232458. Epub 2012, Dec 20. PMID:23258413 doi:10.1126/science.1232458
- ↑ Skeldon AM, Wang L, Sgarioto N, Beveridge RE, Chan S, Dorich S, Dumais V, Fradet N, Gaudreault S, LeGros P, McKay D, Seliniotakis R, Sietsema DV, Zhang L, Boily MO, Burch JD, Caron A, Fader LD, Lama L, Xie W, Patel DJ, Tuschl T, Crackower MA, Pike KA. Structural insight into the cGAS active site explains differences between therapeutically relevant species. Commun Chem. 2025 Mar 22;8(1):88. PMID:40121343 doi:10.1038/s42004-025-01481-7
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